tbuckley/cabot-search huggingface dataset:
Genetic alteration and ctDNA mutation profiling of esophageal cancer in Chinese patients.
Authors: Zeng Qingxin, Yingnan Yang, Gao Zhou, Haihua Jiang, Jia Guo, Shuhua Zhao
Journal: Journal of Clinical Oncology (2023)

e16046 Background: Esophageal cancer is the sixth most common cause of cancer-related mortality. There are two distinct histological types of esophageal cancer: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). In China, ESCC is the major subtype. Higher incidence of EAC is observed in western countries. Liquid biopsy detecting circulating tumor DNA is a non-invasive, real-time and highly sensitive approach that is able to identify and monitor the genetic mutations in tumor. Methods: In this study, we collected 490 Chinese esophageal cancer patients from 2018-2022 and characterized the mutational landscape of esophageal tumor tissue and circulating tumor DNA by whole exome sequencing or deep sequencing of targeted gene panel. The consistency of genetic alteration between tumor and ctDNA was also explored. Results: A total of 176 patients with plasma and 345 patients with cancer tissue were analyzed, among them, 31 patients had both ctDNA and tissue biopsy data. 277 genes with 1257 mutations were identified from plasma samples of 176 patients. The top frequently mutated genes were TP53 (89.1%), KMT2D (24.0%), SYNE1 (14.9%), NOTCH1 (14.3%), EP300 (13.7%), LRP1B (13.7%) and ZNF750 (10.3%). The mutation rates of these genes between ctDNA and tissue biopsy (N = 31 patients) were in concordance by Fisher's exact test (P &gt; 0.05). Most frequent mutations were found in TP53 gene, which account for 89.1% of total plasma samples and 90.4% of tumor tissues. KMT2D gene mutations were detected in 24% of patients which encode histone methyltransferase that methylates the Lys-4 position of histone H3 and regulates transcriptional activation, indicating epigenetic regulation might be involved in the pathogenesis of esophageal cancer. Functional enrichment analysis was performed including Gene Ontology (GO) and KEGG analysis across all the three domains, Biological process, Molecular Function, and Cellular component. The KEGG terms with the highest enrichment score were PI3K−Akt signaling pathway, which is a key driver in carcinogenesis. In addition, we didn’t observe the mutually exclusive mutation or co-occurrence pattern of any gene pairs in our cohort. Conclusions: We demonstrated the utility of liquid biopsy to draw a ctDNA mutation profiling of esophageal cancer in Chinese patients. Genetic mutations identified from ctDNA showed consistency with mutations from tumor tissue.
Chemotherapy and radiofrequency hyperthermia (oncothermia) in the treatment of metastatic colorectal cancer.
Authors: Gulhan Ipek Deniz, Ayten Can, Sualp Tansan
Journal: Journal of Clinical Oncology (2023)

e15569 Background: Colorectal cancer (CRC) is the second leading cause of death in adults. Standard treatment for metastatic disease includes chemotherapy and biological agents. Although more than 50% of patients respond to multi agent chemotherapy, resistance to treatment is a significant problem and more than 85 % of patients die within five years. Radiofrequency hyperthermia (Oncothermia- OT) is a non-invasive treatment modality which utilizes 13 MHz external radiofrequency waves to selectively heat cancer cells to 45 C, contributing to apoptosis, and aggregation of DNA repair enzymes, potentially overcoming resistance and improving chemotherapy efficacy. It has been used alone or in combination with chemotherapy. Since most metastatic CRC patients have disease limited to the abdominal cavity and liver, Oncothermia can be applied with a single electrode covering the entire abdominal cavity, immediately following chemotherapy without additional side effects. Methods: We treated 25 consecutive CRC patients with disease limited to liver and/or abdominal cavity with chemotherapy and biological agents and concomitant weekly OT (Oncotherm-EHY 3010) for one hour to the whole abdomen. Chemotherapy was FOLFIRI in 2, FOLFOX in 6, FOLFIRINOX in 17. Bevacizumab was used with chemotherapy in 22 and cetuximab in 1 patient. Patients were followed by periodic CT/MRI/PET-CT. Treatment duration ranged from 4 to 60 months. Results: No unexpected or grade III-IV toxicity was observed. Complete response was observed in 3 patients, partial response in 21 patients and stable disease in one patient for an objective response rate of 96%. Median follow up is 20.1 months (range 4-82+ months). 16 patients are alive, 3 with no disease and 13 on treatment. 9 patients have died. Conclusions: Although this is a single center retrospective observation, the combination of chemotherapy with Oncothermia appears tolerable and feasible in metastatic CRC. Despite the limitations of this observation, activity of this multi-modality treatment appears promising. Prospective randomized trials are needed to confirm these findings.
Safety and survival in adult women with platinum sensitive relapsed BRCA mutant ovarian cancer: A study of patients in Olaparib Turkey Early Access Program—LynTurk study.
Authors: Ece Esin, Melin Aydan Ahmed, Hasan Çağrı Yıldırım, Nil Molinas Mandel, Engin Erdemoglu, Murat Sari, Adnan Aydiner, Zafer Arik, Mahmut Gumus, Mert Basaran, Ozlem Er, Ali Gokyer, Fatih Kose, Sercan On, Ahmet Ozet, Leyla Özer, Nail Paksoy, Osman sütcüoğlu, Sernaz Uzunoglu, Semra Paydas
Journal: Journal of Clinical Oncology (2023)

e17509 Background: SOLO-2 trial results have proven the efficacy of Olaparib in BRCA-mutant platinum-sensitive relapsed ovarian cancer patients. LynTurk as an open label, multi-center study, designed to show the real world safety and efficacy results of Turkey Olaparib managed access program. Methods: Patients with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy were eligible for Olaparib maintenance in Turkish managed access program. The primary aim was safety. Progression free survival, overall survival were the secondary endpoints. Results: Between December 2014 and March 2021, 48 patients were accepted for program. Due to immaturity of data, in this report, a total of 26 patient results were analyzed. BRCA2 mutation was present in 5 patients, one patient have both BRCA1 and BRCA2 mutations; 20 cases were found to be BRCA1 mutated. The median age of patients was 51 (29-61) years. All patients have high grade serous adenocarcinoma of ovary or primary peritoneal carcinoma. The most common site of involvement are lymph nodes and peritoneal surfaces; in 11% of cases there are liver parenchyma metastasis. All of the patients received at least two lines of platinum-based chemotherapy; median 3 lines (2-4) of treatment were applied before Olaparib maintenance. Previous bevacizumab treatment was allowed in this program, 53.8% of cases were received at least 3 cycles, maintenance bevacizumab was given to 12 patients. Median treatment duration with Olaparib was 26,2 months (3-80m). In 30.7% of cases no adverse events were noted, at least one level dose reduction was needed for 50% of patients due to toxicity. Hematological adverse events were the mostly encountered followed by dyspepsia and fatigue. Anemia was the reason for permanent drug discontinuation in 2 patients (0.7%). No febrile neutropenia was reported. During the follow-up, no secondary malignancy and pneumonitis was noted. Median progression free survival from the end of last chemotherapy was 19.3 months. One-year PFS rate was 88.4% and 2-y PFS rate was 53.8%. One-year OS rate from the end of chemotherapy was 92.3% and 2-year was 61.5%. Conclusions: The real world data from Turkey managed access program has showed that Olaparib has a safety profile in paralel with clinical trials (SOLO). No new safety signals were reported. Although a heterogenous population including heavily pretreated patients, maintenance Olaparib was found effective. This report will be updated as the data of all intent to treat population will gather and will get mature.
Treatments and clinical outcomes in stage II colon cancer (CC) patients (pts) with 12-gene Oncotype DX Colon Recurrence Score assay-guided therapy: Real-world data.
Authors: Baruch Brenner, Yakatherina Shulman, Ayala Hubert, Sofia Man, Ravit Geva, Irit Ben-Aharon, Shlomit Fennig, Moshe Mishaeli, Nirit Yarom, Gil Bar-Sela, Ronen Brenner, Ayelet Shay, Lior Soussan-Gutman, Hillary Voet, Avital Bareket-Samish, Nicky Liebermann
Journal: Journal of Clinical Oncology (2023)

3620 Background: The role of adjuvant chemotherapy (CT) in stage II CC is debated. The validated 12-gene Oncotype DX Colon Recurrence Score test provides a Recurrence Score (RS) result (range, 0-100) which estimates recurrence risk (RR) in stage II/III pts. We studied treatment and clinical outcomes in CC pts in whom treatment decisions incorporated the RS result. Methods: This prospectively designed cohort study included all stage II, MMR-P, CC pts who underwent the 12-gene Oncotype DX testing through Clalit between 1/2011 and 12/2016 and had available data with minimum 3-yr follow-up. Kaplan-Meier (KM) estimates and log-rank tests were used to compare RR and CC specific mortality (CCSM) between RS categories. Multivariable analysis (MVA) identified variables associated with RR/CCSM. Results: The analysis included 938 pts. Median age, 68 (IQR, 60-76) yrs; 96% had T3 tumors, and 89% had ≥12 nodes examined. Median RS was 26 (IQR, 19-33). The 3 RS categories (0-29, 30-40, and 41-100) included 65%, 24%, and 11% of pts, respectively. The overall CT use rate was 24%, with a significant difference between the 3 categories (14%, 36%, and 60%, respectively, P&lt; .0001). Pts with very low RS (0-15) comprised 14% of the cohort (CT use rate, 11%). Younger pts, and those with invasion/perforation/obstruction were more likely to receive CT. Clinical outcomes with a median follow up of 6.9 (IQR, 5.5-8.6) yrs are presented (Table). Among untreated pts, KM estimates for RR and CCSM differed significantly between the 3 RS categories ( P&lt; .0001). Outcome of untreated RS 0-15 pts was excellent. In an MVA model, male sex, presence of invasion/perforation/obstruction and higher RS category (RS 41-100 vs 0-29 and vs 30-40, but not RS 30-40 vs 0-29) were associated with increased RR. For CCSM, the results were similar, but this time age ≥70 yrs replaced sex as a significant prognostic variable. Clinical outcomes within each RS group did not differ significantly between treated and untreated pts, but were numerically better with CT in the RS 41-100 group. Conclusions: This real-world analysis showed that the RS results provide independent prognostic information in stage II CC. Further studies are needed to investigate the potential role of the RS result as a predictor of CT benefit, but the data suggest that this benefit may be limited to pts with high RS results. [Table: see text]
Impact of panel size on minimum residual disease (MRD) assay performance.
Authors: Christopher Jon Battey, Ashley Acevedo, Matt LaBella, Sangita Ganesh, Ravi Patel, Kyle Trettin, Elise Buser, Nafei Xu, Genevieve M. Gould, Dale Muzzey
Journal: Journal of Clinical Oncology (2023)

e15022 Background: Sequencing circulating tumor DNA is a promising method for monitoring cancer treatment response and detecting recurrence, but sensitivity at the low tumor fractions typical of early-stage, post-treatment, and early recurrent tumors is limited by the small number of variants targeted in commercially available assays. Methods: We developed a tumor-informed minimum residual disease (MRD) assay using tumor-normal whole-genome sequencing (WGS) followed by interrogation of select somatic variants in cell-free DNA (cfDNA). We describe theoretical limits on panel designability as a function of tumor purity and sequencing depth using simulations and a discovery cohort of 31 patient samples. cfDNA assay performance was tested by creating serial dilutions of patient plasma before somatic enrichment and sequencing. Simulations and in-silico downsampling of target sites were used to test sensitivity as a function of panel size. A bioinformatics pipeline incorporating somatic calling, copy number inference, error assessment, and tumor-fraction estimation was developed to analyze results. Results: Across a range of tissues, tumor-normal WGS identified from hundreds to tens of thousands of somatic variants to inform an MRD capture panel. 97% of samples tested returned at least 300 high-confidence somatic variants, and targeted sequencing demonstrated over 95% positive predictive value in somatic variant calls. In cfDNA dilution experiments, we observed &gt; 99% sensitivity at a tumor fraction of 0.01%. Expanding the panel size from 16 to 300 target variants increased sensitivity at 0.005% tumor fraction from approximately 20% to &gt; 95%. Our tumor fraction model returned accurate quantification down to the parts per hundred thousand (0.001%) range, even when only a single tumor molecule could be observed at each target site. Conclusions: Increasing the number of targeted variants in an MRD assay increases sensitivity at low tumor fractions, and WGS-driven panel design ensures a sufficient number of interrogated variants while minimizing the failure rate due to panel designability. High sensitivity MRD has the potential to enable earlier recurrence detection while also giving researchers and clinicians new tools for monitoring patient treatment responses.
Bi-directional interaction and predictive potential of inflammatory and oxidative stress-related biomarkers in patients with non-small cell lung cancer.
Authors: Srdjan Nikolovski, Mark Jaradeh, Fakiha Siddiqui, Jeanine Walenga, Walter Jeske, Jawed Fareed, Wickii T. Vigneswaran
Journal: Journal of Clinical Oncology (2023)

e15030 Background: Interplay between oxidative stress and inflammation play major role in the development and progression of various malignancies. As one of the most common and the deadliest malignancy, lung cancer has a prominent vicious cycle of oxidative stress and immune response. The aim of this study is to examine the inter-relationship between basic oxidative stress and inflammation-related plasma biomarkers in patients with non-small cell lung cancer (NSCLC) undergoing surgical resection procedure. Methods: After obtaining informed consent, pre-operative plasma levels of alpha-fetoprotein, nitrotyrosine, urokinase-type plasminogen activator, and myeloperoxidase (MPO) as oxidative stress-related biomarkers were determined in 49 patients with diagnosed NSCLC. In the same patient group, plasma levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and epidermal growth factor were also evaluated. Control samples were obtained from 34 healthy individuals. Plasma biomarkers were determined by enzyme-linked immunosorbent assay. Applicable statistical methods were used to analyze the data. Results: Positive correlation was observed between MPO and levels of the following inflammation-related biomarkers: IL-6 (r = 0.397, p = 0.007), VEGF (r = 0.494, p = 0.001), TNF-α (r = 0.348, p = 0.019), and MCP-1 (r = 0.377, p = 0.011). Biomarkers showing significance in correlation analysis were further analyzed by linear logistic regression in order to determine presence and strength of causality in each direction (oxidative stress to inflammation and inflammation to oxidative stress). IL-6 and VEGF were observed as a predictors of MPO levels (B = 0.334, p = 0.031, and B = 0.391, p = 0.039, respectively). Furthermore, causality was observed in the opposite direction as well. MPO levels were shown as a slightly better predictor of both IL-6 and VEGF plasma levels (B = 0.349, p = 0.007, and B = 0.433, p = 0.001, respectively), but also as a predictor of TNF-α and MCP-1 levels (B = 0.193, p = 0.019, and B = 0.217, p = 0.011, respectively). Conclusions: Conclusion: These studies showed a strong correlation between measured oxidative stress-related and inflammatory biomarkers. Furthermore, these observations underscore the importance of oxidative stress in the pathogenesis of lung cancer.
Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody for unresectable hepatocellular carcinoma (uHCC): A retrospective analysis.
Authors: Linan Yin, Ruibao Liu, Shijie Li, Xunbo Hou
Journal: Journal of Clinical Oncology (2023)

e16163 Background: Chemoembolization plus hepatic arterial infusion chemotherapy significantly improved ORR and PFS over chemoembolization alone in patients with uHCC in previous study. And donafenib showed the survival benefit and better safety compared with sorafenib in a Phase III trial. In consideration of synergism, we evaluated the safety and efficacy of TACE plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody in patients with uHCC. Methods: We retrospectively analyzed the patients who were diagnosed as unresectable hepatocellular carcinoma and received the treatment of TACE plus HAIC combined with donafenib, anti-PD-1 antibody as first-line therapy from Nov 2021 to Nov 2022 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS), time to response (TTR) and safety. Results: Of 36 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m 2 2h, leucovorin 400 mg/m 2 1h, fluorouracil bolus 400 mg/m 2 in the first 10 minutes, and fluorouracil infusion 2400 mg/m 2 for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (range, 44-80). The study population was predominantly male (75%), and 89% were HBV-positive. Patients were classified as BCLC stage A (8.3%), stage B (8.3%) and stage C (83.4%). The rates of patients with portal vein tumor thrombus and extrahepatic metastasis were 69% and 11% respectively. 30.6% patients received interventional therapy before the combination treatment. By Feb 2023, 23 patients had received at least one imaging evaluation, 19(82.6%) of them achieved partial response, ORR and DCR were 82.6% and 100% per modified RECIST criteria respectively. And the median TTR was 1.1 months. With 3.8 months of median follow-up time, the 6-month PFS rate was 51.2%. The median PFS and OS were not reached. All 36 patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 8 (22.2%) patients, and no grades 4 or 5 were reported. The most common TRAEs included alanine aminotransferase increased (77.8%), alkaline phosphatase increased (77.8%), platelet count decreased (69.4%) and blood bilirubin increased (63.9%). Conclusions: Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody are effective and tolerable for uHCC patients.
Artificial neural network model analysis in T790M detection after failure of first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors.
Authors: Adam Pluzanski, Dariusz Świetlik, Maciej Jerzy Krzakowski
Journal: Journal of Clinical Oncology (2023)

e21041 Background: Despite osimertinib availability, first or second generation (1st/2nd gen.) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are commonly used in many countries. Clinical factors identified before first line EGFR TKIs treatment that correlate with T790M occurrence are not well-known. In this single center retrospective study we define the artificial intelligence-based model that support T790M detection in daily practice. Methods: In 80 patients (pts) consecutively progressed on 1st/2nd generation EGFR TKIs T790M mutation was assessed. In multivariate logistic regression factors predictive to T790M mutation were identified. Based on clinical and molecular factors present before EGFR TKIs initiation multi-layer perceptron (MLP) neural network was used for building model classifying patients according to T790M status. The artificial neural network consisted of three layers: input, hidden and output layers of 36, 6 (optimally due to the result of the neural network) and 1 neurons, respectively. During the learning process the weight links between the neurons were modified using Broyden-Fletcher-Goldfarb-Shanno algorithm. To calculate the diagnostic quality of the artificial neural network, we divided at random of all patients for two groups: training and testing. The training group contained 65 and testing group 15 cases. Sensitivity and specificity for both models were assessed. TIBCO Software Inc., Statistica (data analysis software system), version 13 software was used for all calculations. Results: In 49/80 pts (61.3%) T790M was present. In logistic regression model: del19 EGFR mutation, chest or liver metastases and 1st gen. TKI treatment correlated with T790M presence. Parameters included in building neural network model were: del19/L858R/other EGFR mutation status, sex, age, 1st/2nd gen. TKI in first line, clinical stage, metastases location, ECOG PS, smoking history. Learning and testing phase models detected T790M with sensitivity-94.7%, specificity – 91.3% and sensitivity-77.8%, specifity-83.3%. In testing set (15 pts) proposed neural network model achieved 80% accuracy in predicting correctly T790M status. Clinical stage, TKI generation in first line, metastases location, EGFR mutation were the most valuable entrance parameters. After conducting a sensitivity analysis for all 8 the analysed variables the observed error quotients were above 1, therefore, they are all significance and should be entered as input to the developed network. Conclusions: The proposed artificial neural network model used parameters identified before start of TKI treatment and achieved high accuracy in T790M status prevalence. Although this model need to be validated in large cohort it can be an useful tool to support clinicians decision.